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Summary Background:  The role of digoxin in the prognosis of patients with heart failure (HF) remains unclear. Aims:  To evaluate the relationship of commencing treatment with digoxin (CTDig) with the mortality and the morbidity of patients with HF. Methods:  Prospective study over 8 years on 4467 patients with HF. Main outcomes were all‐cause and cardiovascular mortality, hospitalisations and visits. We analyse the independent relationship of CTDig, with the mortality and the morbidity, stratifying patients for cardiovascular comorbidity, after propensity score‐matching for potential confounders (1421 patients who CTDig vs. another 1421 patients non‐exposed to digoxin). Results:  During a median follow up of 46.1 months, 1872 patients (65.9%) died, and 2203 (77.5%) were hospitalised. CTDig was associated with a lower all‐cause mortality (HR = 0.90 [95% CI, 0.84–0.97]), and cardiovascular mortality (HR = 0.87 [0.81–0.96]), hospitalisation (HR = 0.91 [0.86–0.97]), 30‐day readmission for HF (HR = 0.88 [0.79–0.95]), and visits (HR = 0.94 [0.90–0.98]) (p < 0.001 in all cases), after adjustment for the propensity to take digoxin, other medications, and other potential confounders. These effects of digoxin were independent of gender, or type of HF (systolic or non‐systolic). Conclusion:  The data suggest that therapy with digoxin is associated with an improved mortality and morbidity of HF, including women and patients with non‐systolic HF.